Summary ! This proposal will support an outstanding Research Specialist who is essential to the scientific direction and operation of a productive research group. The Research Specialist and Unit Director have worked closely since 2010 and have generated a significant number of high quality publications that have had a major impact on the field. The major goal of this group is to pursue mechanisms that contribute to the aggressive behavior of poorly differentiated carcinomas and to use the information obtained to improve therapy. Specific projects focus on the role of integrins and VEGF receptors, especially within the context of cancer stem cells (CSCs). The Research Specialist has superb expertise in the study of integrins and growth factor receptors, as well as the use of animal models. He also has a strong interest in translational research and he has been able to apply the knowledge generated from his work to design more effective therapies for breast and prostate cancer. The Research Specialist is essential for the proposed work of the group over the next five years, which involves new directions and collaborations. Importantly, he has been able to build strong and productive collaborations with leading experts in related fields to diversify and enhance the impact of the group?s research program. These interactions have enabled the Research Specialist and Unit Director to formulate three major goals/hypotheses to be studied over the next five years, which are inter-related. The contributions of the Research Specialist are essential for completing these goals. The first goal will focus on how integrins contribute to the dynamic plasticity of carcinoma cells and heterotypic interactions between CSCs and non- stem tumor cells. The second goal will study how integrins promote resistance to a novel form of cell death termed ferroptosis. The final goal will investigate molecules and unravel mechanisms that promote the differentiation of CSCs, and exploit the data obtained to improve therapy. In summary, The Research Specialist is capable of making significant and innovative contributions to the biology and therapy of aggressive carcinomas, as evidenced by his accomplishments and sustained productivity. This award will provide him the freedom and security to advance his research and to support the research program of the Mercurio group.